Abnormal vascular smooth muscle migration and proliferation is associated with cardiovascular disorders such as atherosclerosis, hypertension and most endovascular procedures. Abnormal vascular smooth muscle migration and proliferation is a common complication of percutaneous transluminal coronary angioplasty (PTCA). The incidence of chronic restenosis resulting from vascular smooth muscle proliferation following PTCA has been reported to be as high as 40-45% within 3-6 months. Capron, L., Huedes, D., Chajara, A. and Bruneval, P. (1991) J. Cardiovasc. Pharmacol., 18, 207-211; Bourassa, M. (1992) J. Am. Coil. Cardiol., 19, 1410-1411. Several neurohumoral factors, including angiotensin II and norepinephrine, as well as growth factors, including platelet-derived growth factor (PDGF) and basic fibroblast growth factor (FGF), have been implicated in the development of vascular restenosis in vivo. Bourassa, M. et al. supra; Powell, J. S., Clozel, J. P., Muller, R. K. M., Kuhn, H., Hefti, F., Hosang, M. and Baumgartner, H. R. (1989) Science, 245, 186-198; Clozel, J. P., Hess, P., Michael, C., Schietinger, K. and Hypertension, 18(Suppl. II), 1155-1159; Fingerle, J., Sanders, K. H. and Fotev, Z. (1991) Basic Res. Cardiol., 86, 75-81; Fomey-Prescott, M., Webb, R. L. and Reidy, M.A. (1991) Am. J. Pathol., 139, 1291-1296; Kauffman, R. F., Bean, J. S., Zimmerman, K. M., Brown, R. F. and Steinberg, M. I. (1991) Life Sci., 49, 223-228; Azuma, H. Y. and Hamasaki, H. (1992 ) Br. J. Pharmacol., 106, 665-671; Ferns, G. A. A., Raines, E. W., Sprugel, K. H., Motani, A. S., Reidy, M. A. and Ross, R. (1991) Science, 253, 1129-1132; and Lindner, V. and Reidy, M. A. (1991) Proc. Natl. Acad. Sci. (USA), 88, 3739-3743.
The high incidence of vascular reocclusion associated with PTCA has led to the development of in vivo animal models of restenosis and the search for agents to prevent restenosis. Angiotensin II receptor antagonists, angiotensin converting enzyme (ACE) inhibitors, .alpha.-adrenoreceptor antagonists and growth factor antibodies have generally produced only a modest (10-50%) reduction of vascular restenosis in such animal models. Powell, J. S., et al., supra; Fingerle, J. et al., supra; Forney-Prescott, M. et al., supra; and Kauffman, R. F., et al., supra. Clinical studies with ACE inhibitors (which showed only a moderate protective effect in animal models of restenosis) have failed to demonstrate a significant efficacy in the prevention of angiographically-defined restenosis in humans. Popma, J. J., Califf, R. M. and Topol, E. J. (1991) Circulation, 84, 426-1436. This limited or insignificant protection against vascular restenosis affected by agents with specific mechanisms of action most likely reflects the complex nature of the pathophysiology underlying vascular restenosis. A multiplicity of chemotactic and mitogenic factors are believed to be involved in this response to vascular wall injury, and it is likely that interfering with the actions of only one of these factors will prove to be beneficial.
Therefore, therapeutic anti-mitotic agents which reduce or inhibit the abnormal migration and proliferation of smooth muscle cells associated with cardiovascular disorders such as atherosclerosis and vascular hypertrophy associated with hypertension, or resulting from complications following PTCA and causing chronic restenosis are highly desirable.